The Human Immunodeficiency Virus Type 1, (HIV-1) induces a strong humoral immune response in humans and animals to virtually all of its viral antigens. Despite neutralizing antibody responses in humans and chimpanzees, humoral immune defenses fail to protect from initial infection (chimpanzee model) or progression to AIDS (human infection). This is critically important since successful vaccine development has depended historically on humoral responses to the vaccine for antiviral protection. Although a variety of hypotheses such as cell-to-cell virus transmission or inadequate cell-mediated immune responses have been suggested to explain this lack of protection, none have proved an adequate explanation to date. Our group first reported in 1987 and definitively demonstrated in early 1988 the presence of antibodies in the serum of HIV-1 infected individuals which enhance HIV-1 infection in vitro. By mid 1988, the presence of enhancing antibodies was confirmed by several laboratories in the United States and Europe. Moreover, two mechanisms for antibody- dependent enhancement (ADE) have been identified. One utilizes the alternative pathway of complement, antibody to HIV-1, and cellular complement receptors (C'-ADE while the other utilizes antibody to HIV-1 and cellular Fc receptors (FcR-ADE). The C'-ADE mechanism has been demonstrated to abrogate the protective effects of neutralizing antibodies and to be composed of antibodies which bind to antigenic domains separate from neutralizing domains, it is critical to the NIAID mission of developing an HIV-1 vaccine to ascertain the role of HIV-1 enhancing antibodies in the pathogenesis of AIDS. Our research will focus on a comparable analysis of the intracellular and extracellular mechanisms of C'-ADE and FcR-ADE. These studies will utilize both standardized cell lines which magnify the ADE effect and human primary monocyte/macrophage cultures. Using human monoclonal antibodies to HIV-1 which mediate C'-ADE of HIV-1 infection, we will determine whether both systems of enhancement are induced by common antigenic epitopes. Relevance to in vivo pathogenesis will be examined in humans by correlating disease status and disease progression with ADE titers as well as neutralizing titers of both tissue culture-derived HIV- 1 (HTLV-III(B)isolate) or autologous clinical isolates of HIV. We will concommitantly explore the utility of macaques infected with simian immunodeficiency virus (SIV) as an in vivo model system. These studies will address the role of enhancing antibody in HIV and SIV pathogenesis and their importance in AIDS vaccine development.